CD123 IL-3R (α chain)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
B Cell
Hematopoietic Cell
Eosinophil
Monocyte
Megakaryocyte
Erythroid Cell
Myeloid Cell
Leukemia cell
Granulocyte
Progenitor Cell
Macrophage
Basophil
Testis
Endothelial Cell
Mast Cell
Bone Marrow
Placenta
Brain
Lymphoma Cell
Stromal Cell
70 / 70

Expression
CD123 is expressed on bone marrow multipotential hematopoietic stem/ precursors, most myeloid cell lineages including eosinophils and basophils but not neutrophils.  Expression is on monocytes, granulocytes, macrophages, mast cells, a subpopulation of CD5+ B cells and megakaryocyte committed precursors and on the erythroid lineage.  It is also present on some myelocytic leukemias and pre-B lymphomas and leukemias.  Expression is on hematopoietic progentitor cells, some endothelial cells, Leydig cells of the testis, placenta, brain and possibly on stromal progenitor cells.

Structure
MOLECULAR FAMILY NAME: Belongs to the hemopoietin receptor family.

CD123 is a signal pass-type 1 a chain glycopeptide.  It contains a 288 aa extracellular region which contains an 100 aa N-terminal domain (similar to that found in CD116 and CD125) followed by a 200 aa fibronectin type-3 domain containing a WSXWS motif, both of which are required for IL-3 binding and 9 potential N-glycosylation sites,  a 20 aa transmembrane region and a 52 aa cytoplasmic region which is essential for signal propagation.  There is 1 unit of class I receptor motif in the extracellular region and no intrinsic enzymatic activity in the cytoplasmic region.  The IL-3R is formed by the association of CD123 and a common b chain CD131 that is also a component of the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5.  CD123 is a cytokine receptor belonging to the hemopoietin receptor superfamily and the Ig gene superfamily. 

MOLECULAR MASS
Cell Type Unreduced Reduced
Myeloid cells 70 kDa

POST-TRANSCRIPTIONAL MODIFICATION: No information.

POST-TRANSLATIONAL MODIFICATION

CD123 has nine N-glycosylation sites.


Ligands
CD123 binds IL-3R with a very low affinity of kDa = 80-90 nM but it forms a high affinity in association with CD131.  A 110 kDa Ser/Thr kinase that is activated following IL-3R stimulation has been shown to be constitutively associated with the IL-3R.

LIGANDS AND MOLECULES ASSOCIATED WITH CD123
Molecule Comment
CD131 CD123 forms heterodimer with CD131 to form receptor for IL-3.  (CD131 is also a component of the GM-CSF and IL-5 receptors)
IL-3 CD123 binds IL-3 with low affinity and forms a high affinity with CD123


Function
CD123 is the primary binding subunit of the IL-3Rα chain and is associated with CD131 (common to IL-5 and GM-CSF receptors to form the functional IL-3R.  The ligation of IL-3R by IL-3 promotes differentiation and proliferation of multipotential stem/progenitor cells as well as monocyte, neutrophil, basophil and eosinophil bone marrow precursors.  IL-3 binding to IL-3R stimulates the proliferation or eythroid and megakaryocyte committed precursors and induces activation of neutrophils and monocytes.  The cytoplasmic domain is involved in the activation of STAT5 and proliferation, whereas the distal region is linked to cell survival.  Several strains of naturally CD123-deficient mice exist that are hyporesponsive to IL-3 but do not show any overt abnormalilty in hematopoiesis even when challenged with parasites or bacterial pathogens.  Also CD123 knockout mice have no gross abnormalities which suggests that there is functional redundancy of cytokines, allowing the maintenance of hematopoiesis.  In the mouse, IL-3R also activates mast and pre-B cells.  CD123 induces the Tyr phosphorylation of several proteins and activates Ras and the signaling mechanisms.

BIOCHEMICAL ACTIVITY

CD123 binds the IL-3 ligand.

DISEASE RELEVANCE AND FUNCTION OF CD123 IN INTACT ANIMAL

CD123 is a marker for stem cell populations and assists in the diagnosis of acute myeloid leukemias and B lymphoproliferative disorders.  It is a therapeutic target in the treatment of various tumors using IL-3R antagonists, anti-CD123 mAb conjugated to cytotoxic agents, or by stimulating leukemic cells into the cell cycle, thereby making them the susceptible to cytotoxic agents and is the target of IL-3 therapy for improving multilineage hematopoietic recovery in myelosuppression or after myeloablative chemotherapy.

Comments
In the mouse, 2 proteins with a 91% aa sequence identity have been identified, the AIC2A and the AIC2B proteins.  Both AIC2A and AIC2B can associate with the murine CD123 orthologue to form a distinct high affinity IL-3Rs.  The AIC2B protein is a common component of the murine IL-3R, IL-5R and GM-CSFR.  The overall sequence of both proteins is similar to that of human CD131.  The human CD123 gene has been mapped to the pseudoautosomal region of the X and Y chromosome.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD123: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD123: No information.

ADDITIONAL INSIGHTS

The mouse IL-3R a subunit interacts with the common b subunit as well as the IL-3b subunit is present in the mouse but not in humans.  Some strains of mice express low levels of CD123 and bone marrow cells from these mice are hyporesponsive to IL-3.  The low level expression is due to the alternative splicing that skips exon 8.  This is caused by deletion of 5 bases at the branch point in intron 7.



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3563P26951
MouseP26954M29855
MouseP26955M34397
MouseP26952X64534
Antibodies
7G3   View Reactivity
9F5   View Reactivity

Revised June 25, 2008


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